tbuckley/cabot-search huggingface dataset:
Evolution of Epidermal Growth Factor (EGF)-like and Zona Pellucida Domains Containing Shell Matrix Proteins in Mollusks
Authors: Keisuke Shimizu, Takeshi Takeuchi, Lumi Negishi, Hitoshi Kurumizaka, Isao Kuriyama, Kazuyoshi Endo, Michio Suzuki
Journal: Molecular Biology and Evolution (2022)

Abstract Several types of shell matrix proteins (SMPs) have been identified in molluskan shells. Their diversity is the consequence of various molecular processes, including domain shuffling and gene duplication. However, the evolutionary origin of most SMPs remains unclear. In this study, we investigated the evolutionary process EGF-like and zona pellucida (ZP) domains containing SMPs. Two types of the proteins (EGF-like protein (EGFL) and EGF-like and ZP domains containing protein (EGFZP)) were found in the pearl oyster, Pinctada fucata. In contrast, only EGFZP was identified in the gastropods. Phylogenetic analysis and genomic arrangement studies showed that EGFL and EGFZP formed a clade in bivalves, and their encoding genes were localized in tandem repeats on the same scaffold. In P. fucata, EGFL genes were expressed in the outer part of mantle epithelial cells are related to the calcitic shell formation. However, in both P. fucata and the limpet Nipponacmea fuscoviridis, EGFZP genes were expressed in the inner part of the mantle epithelial cells are related to aragonitic shell formation. Furthermore, our analysis showed that in P. fucata, the ZP domain interacts with eight SMPs that have various functions in the nacreous shell mineralization. The data suggest that the ZP domain can interact with other SMPs, and EGFL evolution in pterimorph bivalves represents an example of neo-functionalization that involves the acquisition of a novel protein through gene duplication.
A truncated reverse transcriptase enhances prime editing by split AAV vectors
Authors: Zongliang Gao, Sujan Ravendran, Nanna S. Mikkelsen, Jakob Haldrup, Huiqiang Cai, Xiangning Ding, Søren R. Paludan, Martin K. Thomsen, Jacob Giehm Mikkelsen, Rasmus O. Bak
Journal: Molecular Therapy (2022)

Prime editing is a new CRISPR-based, genome-editing technology that relies on the prime editor (PE), a fusion protein of Cas9-nickase and M-MLV reverse transcriptase (RT), and a prime editing guide RNA (pegRNA) that serves both to target PE to the desired genomic locus and to carry the edit to be introduced. Here, we make advancements to the RT moiety to improve prime editing efficiencies and truncations to mitigate issues with adeno-associated virus (AAV) viral vector size limitations, which currently do not support efficient delivery of the large prime editing components. These efforts include RT variant screening, codon optimization, and PE truncation by removal of the RNase H domain and further trimming. This led to a codon-optimized and size-minimized PE that has an expression advantage (1.4-fold) and size advantage (621 bp shorter). In addition, we optimize the split intein PE system and identify Rma-based Cas9 split sites (573-574 and 673-674) that combined with the truncated PE delivered by dual AAVs result in superior AAV titer and prime editing efficiency. We also show that this minimized PE gives rise to superior lentiviral vector titers (46-fold) over the regular PE in an all-in-one PE lentiviral vector. We finally deliver the minimized PE to mouse liver by dual AAV8 vectors and show up to 6% precise editing of the PCSK9 gene, thereby demonstrating the value of this truncated split PE system for in vivo applications.
Performance bonuses and the quality of primary health care delivered by family health teams in Brazil: A difference-in-differences analysis
Authors: Nasser Fardousi, Everton Nunes da Silva, Roxanne Kovacs, Josephine Borghi, Jorge O. M. Barreto, Søren Rud Kristensen, Juliana Sampaio, Helena Eri Shimizu, Luciano B. Gomes, Letícia Xander Russo, Garibaldi D. Gurgel, Timothy Powell-Jackson
Journal: PLoS Medicine (2022)

Background Pay-for-performance (P4P) programmes to incentivise health providers to improve quality of care have been widely implemented globally. Despite intuitive appeal, evidence on the effectiveness of P4P is mixed, potentially due to differences in how schemes are designed. We exploited municipality variation in the design features of Brazil’s National Programme for Improving Primary Care Access and Quality (PMAQ) to examine whether performance bonuses given to family health team workers were associated with changes in the quality of care and whether the size of bonus mattered. Methods and findings For this quasi-experimental study, we used a difference-in-differences approach combined with matching. We compared changes over time in the quality of care delivered by family health teams between (bonus) municipalities that chose to use some or all of the PMAQ money to provide performance-related bonuses to team workers with (nonbonus) municipalities that invested the funds using traditional input-based budgets. The primary outcome was the PMAQ score, a quality of care index on a scale of 0 to 100, based on several hundred indicators (ranging from 598 to 660) of health care delivery. We did one-to-one matching of bonus municipalities to nonbonus municipalities based on baseline demographic and economic characteristics. On the matched sample, we used ordinary least squares regression to estimate the association of any bonus and size of bonus with the prepost change over time (between November 2011 and October 2015) in the PMAQ score. We performed subgroup analyses with respect to the local area income of the family health team. The matched analytical sample comprised 2,346 municipalities (1,173 nonbonus municipalities; 1,173 bonus municipalities), containing 10,275 family health teams that participated in PMAQ from the outset. Bonus municipalities were associated with a 4.6 (95% CI: 2.7 to 6.4; p &lt; 0.001) percentage point increase in the PMAQ score compared with nonbonus municipalities. The association with quality of care increased with the size of bonus: the largest bonus group saw an improvement of 8.2 percentage points (95% CI: 6.2 to 10.2; p &lt; 0.001) compared with the control. The subgroup analysis showed that the observed improvement in performance was most pronounced in the poorest two-fifths of localities. The limitations of the study include the potential for bias from unmeasured time-varying confounding and the fact that the PMAQ score has not been validated as a measure of quality of care. Conclusions Performance bonuses to family health team workers compared with traditional input-based budgets were associated with an improvement in the quality of care.
Towards a computational network theory of social groups
Authors: Daniel Redhead, Riana Minocher, Dominik Deffner
Journal: Behavioral and Brain Sciences (2022)

Abstract Network theory is necessary for the realization of cognitive representations and resulting empirical observations of social groups. We propose that the triadic primitives denoting individual roles are multilayer, with positive and negative relations feeding into cost–benefit calculations. Through this, we advance a computational theory that generalizes to different scales and to contexts where conflict is not present.
Enzyme‐Mediated Alleviation of Peroxide Toxicity in Self‐Oxygenating Biomaterials (Adv. Healthcare Mater. 13/2022)
Authors: Niels G. A. Willemen, Shabir Hassan, Melvin Gurian, Maria Fernanda Jasso‐Salazar, Kai Fan, Haihang Wang, Malin Becker, Iris E. Allijn, Ayça Bal‐Öztürk, Jeroen Leijten, Su Ryon Shin
Journal: Advanced Healthcare Materials (2022)
Soft Wireless Bioelectronics Designed for Real‐Time, Continuous Health Monitoring of Farmworkers (Adv. Healthcare Mater. 13/2022)
Authors: Yun‐Soung Kim, Jihoon Kim, Roxana Chicas, Nezahualcoyotl Xiuhtecutli, Jared Matthews, Nathan Zavanelli, Shinjae Kwon, Sung Hoon Lee, Vicki S. Hertzberg, Woon‐Hong Yeo
Journal: Advanced Healthcare Materials (2022)
Lymph node excisions provide more precise lymphoma diagnoses than core biopsies: a French Lymphopath network survey
Authors: Charlotte Syrykh, Charlotte Chaouat, Elsa Poullot, Nadia Amara, Virginie Fataccioli, Marie Parrens, Alexandra Traverse-Glehen, Thierry-Jo Molina, Luc Xerri, Laurent Martin, Romain Dubois, Vanessa Lacheretz-Szablewski, Marie-Christine Copin, Anne Moreau, Marie-Pierre Chenard, Bastien Cabarrou, Amélie Lusque, Philippe Gaulard, Pierre Brousset, Camille Laurent
Journal: Blood (2022)
Identification of a cytokine-dominated immunosuppressive class in squamous cell lung carcinoma with implications for immunotherapy resistance
Authors: Minglei Yang, Chenghao Lin, Yanni Wang, Kang Chen, Haiyue Zhang, Weizhong Li
Journal: Genome Medicine (2022)

Immune checkpoint blockade (ICB) therapy has revolutionized the treatment of lung squamous cell carcinoma (LUSC). However, a significant proportion of patients with high tumour PD-L1 expression remain resistant to immune checkpoint inhibitors. To understand the underlying resistance mechanisms, characterization of the immunosuppressive tumour microenvironment and identification of biomarkers to predict resistance in patients are urgently needed.Our study retrospectively analysed RNA sequencing data of 624 LUSC samples. We analysed gene expression patterns from tumour microenvironment by unsupervised clustering. We correlated the expression patterns with a set of T cell exhaustion signatures, immunosuppressive cells, clinical characteristics, and immunotherapeutic responses. Internal and external testing datasets were used to validate the presence of exhausted immune status.Approximately 28 to 36% of LUSC patients were found to exhibit significant enrichments of T cell exhaustion signatures, high fraction of immunosuppressive cells (M2 macrophage and CD4 Treg), co-upregulation of 9 inhibitory checkpoints (CTLA4, PDCD1, LAG3, BTLA, TIGIT, HAVCR2, IDO1, SIGLEC7, and VISTA), and enhanced expression of anti-inflammatory cytokines (e.g. TGFβ and CCL18). We defined this immunosuppressive group of patients as exhausted immune class (EIC). Although EIC showed a high density of tumour-infiltrating lymphocytes, these were associated with poor prognosis. EIC had relatively elevated PD-L1 expression, but showed potential resistance to ICB therapy. The signature of 167 genes for EIC prediction was significantly enriched in melanoma patients with ICB therapy resistance. EIC was characterized by a lower chromosomal alteration burden and a unique methylation pattern. We developed a web application ( http://lilab2.sysu.edu.cn/tex & http://liwzlab.cn/tex ) for researchers to further investigate potential association of ICB resistance based on our multi-omics analysis data.We introduced a novel LUSC immunosuppressive class which expressed high PD-L1 but showed potential resistance to ICB therapy. This comprehensive characterization of immunosuppressive tumour microenvironment in LUSC provided new insights for further exploration of resistance mechanisms and optimization of immunotherapy strategies.
Monkeypox outbreak predominantly affecting men who have sex with men, Madrid, Spain, 26 April to 16 June 2022
Authors: Jesús Iñigo Martínez, Elisa Gil Montalbán, Susana Jiménez Bueno, Fernando Martín Martínez, Alba Nieto Juliá, Jesús Sánchez Díaz, Natividad García Marín, Esther Córdoba Deorador, Antonio Nunziata Forte, Marcos Alonso García, Ana María Humanes Navarro, Laura Montero Morales, María José Domínguez Rodríguez, Manuel Carbajo Ariza, Luis Miguel Díaz García, Nelva Mata Pariente, Mercedes Rumayor Zarzuelo, Manuel José Velasco Rodríguez, Andrés Aragón Peña, Elena Rodríguez Baena, Ángel Miguel Benito, Ana Pérez Meixeira, María Ordobás Gavín, María Ángeles Lopaz Pérez, Araceli Arce Arnáez
Journal: Eurosurveillance (2022)

Up to 22 June 2022, 508 confirmed cases of monkeypox (MPX) have been reported in the Madrid region of Spain, 99% are men (n = 503) with a median age of 35 years (range: 18–67). In this ongoing outbreak, 427 cases (84.1%) reported condomless sex or sex with multiple partners within the 21 days before onset of symptoms, who were predominantly men who have sex with men (MSM) (n = 397; 93%). Both the location of the rash, mainly in the anogenital and perineal area, as well as the presence of inguinal lymphadenopathy suggest that close physical contact during sexual activity played a key role in transmission. Several cases reported being at a sauna in the city of Madrid (n = 34) or a mass event held on the Spanish island of Gran Canaria (n = 27), activities which may represent a conducive environment for MPX virus spread, with many private parties also playing an important role. Because of the rapid implementation of MPX surveillance in Madrid, one of the largest outbreaks reported outside Africa was identified. To minimise transmission, we continue to actively work with LGBTIQ+ groups and associations, with the aim of raising awareness among people at risk and encouraging them to adopt preventive measures.
The GMC has allowed itself to become the “paramilitary wing” of the NHS
Authors: Andrew J Ashworth
Journal: BMJ (2022)

Distension of the small intestine can play a role in the pathogenesis of various functional intestinal disorders. This study determined the role of vasoactive intestinal polypeptide (VIP) in the adaptative response of intestinal smooth muscle to acute and chronic distension of the ileum <i>in vivo.</i> Several <i>in vitro</i>experiments were performed to identify the mechanism of receptor regulation. Distension was applied by a balloon inflated with air in the ileum either during a single episode in anesthetized or repeatedly in conscious guinea pigs. Then, muscle cells were isolated by enzymatic digestion from the distended and nondistended adjacent ileal segments. In addition, <i>in vitro</i> experiments were performed on freshly dispersed cells for determination of mechanisms. Control cells maximally relaxed (Cmax) at 1 μM VIP (EC<sub>50</sub> = 50 pM) and 100 μM isoproterenol (EC<sub>50</sub> = 7 nM). Both acute and chronic distensions triggered a right-ward shift of the concentration-response curves for VIP (Cmax = 100 μM, EC<sub>50</sub> = 10 nM). A desensitization of the relaxing effect of VIP receptors was also observed when cells were preincubated for 30 min<i>in vitro</i> with VIP. By contrast, the relaxing effect of isoproterenol was affected neither by <i>in vivo</i> distension nor by <i>in vitro</i> incubation with isoproterenol. Desensitization of VIP receptors was prevented by <i>in vitro</i> incubation of cells with VIP plus a VIP antagonist [(d-P-Cl-Phe<sup>6</sup>,Leu<sup>17</sup>)VIP] and by intraluminal perfusion of the VIP antagonist during acute distention<i>in vivo.</i> Moreover, desensitization of VIP receptors did not occur after 30 min preincubation with either forskolin or 8-Bromo-cyclic AMP. These results indicate that mechanical distension of the ileum induces a homologous desensitization of VIP receptors on circular smooth muscle cells, which requires the occupation of its receptors by VIP.
Shared intentionality and the representation of groups; or, how to build a socially adept robot
Authors: Ben Phillips
Journal: Behavioral and Brain Sciences (2022)

Abstract Pietraszewski provides a compelling case that representations of certain interaction-types are the “cognitive primitives” that allow all tokens of group-in-conflict to be represented within the mind. Here, I argue that the folk concept GROUP encodes shared intentions and goals as more central than these interaction-types, and that providing a computational theory of social groups will be more difficult than Pietraszewski envisages.
2022 Presidential Address: Advancing Equitable Cancer Care Through Innovation
Authors: Everett E. Vokes
Journal: Journal of Clinical Oncology (2022)

Article Tools PRESIDENTIAL ADDRESS Article Tools OPTIONS & TOOLS Export Citation Track Citation Add To Favorites Rights & Permissions COMPANION ARTICLES No companion articles ARTICLE CITATION DOI: 10.1200/JCO.22.01305 Journal of Clinical Oncology - published online before print July 7, 2022 PMID: 35797507 2022 Presidential Address: Advancing Equitable Cancer Care Through Innovation Everett E. Vokes , MD, FASCO1,2xEverett E. VokesSearch for articles by this author Show More 1ASCO, Alexandria, VA2University of Chicago, Chicago, IL https://doi.org/10.1200/JCO.22.01305 First Page Full Text PDF Figures and Tables © 2022 by American Society of Clinical OncologyAUTHOR'S DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST2022 Presidential Address: Advancing Equitable Cancer Care Through InnovationThe following represents disclosure information provided by the author of this manuscript. All relationships are considered compensated unless otherwise noted. Relationships are self-held unless noted. I = Immediate Family Member, Inst = My Institution. Relationships may not relate to the subject matter of this manuscript. For more information about ASCO's conflict of interest policy, please refer to www.asco.org/rwc or ascopubs.org/jco/authors/author-center.Open Payments is a public database containing information reported by companies about payments made to US-licensed physicians (Open Payments).Everett E. VokesStock and Other Ownership Interests: Coordination Pharmaceuticals, McKessonHonoraria: Radius Health (I), Takeda (I), Ascendis Pharma (I)Consulting or Advisory Role: Radius Health (I), Takeda (I), Ascendis Pharma (I), BMS, EMD SeronoResearch Funding: AbbVie, Bristol Myers Squibb, Celgene, Novartis, Lilly (Inst)Open Payments Link: https://openpaymentsdata.cms.gov/physician/930740No other potential conflicts of interest were reported.
Signals and cues of social groups
Authors: Gregory A. Bryant, Constance M. Bainbridge
Journal: Behavioral and Brain Sciences (2022)

Abstract A crucial factor in how we perceive social groups involves the signals and cues emitted by them. Groups signal various properties of their constitution through coordinated behaviors across sensory modalities, influencing receivers' judgments of the group and subsequent interactions. We argue that group communication is a necessary component of a comprehensive computational theory of social groups.
Dextran sodium sulfate potentiates NLRP3 inflammasome activation by modulating the KCa3.1 potassium channel in a mouse model of colitis
Authors: Bo Zeng, Yuanting Huang, Siyuan Chen, Rong Xu, Lihui Xu, Jiahao Qiu, Fuli Shi, Siying Liu, Qingbing Zha, Dongyun Ouyang, Xianhui He
Journal: Cellular and Molecular Immunology (2022)
Four-year follow-up of LCAR-B38M in relapsed or refractory multiple myeloma: a phase 1, single-arm, open-label, multicenter study in China (LEGEND-2)
Authors: Wan-Hong Zhao, Bai-Yan Wang, Li-Juan Chen, Wei-Jun Fu, Jie Xu, Jie Liu, Shi-Wei Jin, Yin-Xia Chen, Xing-Mei Cao, Yun Yang, Yi-Lin Zhang, Fang-Xia Wang, Peng-Yu Zhang, Bo Lei, Liu-Fang Gu, Jian-Li Wang, Hui Zhang, Ju Bai, Yan Xu, Han Zhu, Juan Du, Hua Jiang, Xiao-Hu Fan, Jian-Yong Li, Jian Hou, Zhu Chen, Wang-Gang Zhang, Jian-Qing Mi, Sai-Juan Chen, Ai-Li He
Journal: Journal of Hematology & Oncology (2022)

Abstract Background LCAR-B38M is a chimeric antigen receptor T cell product with two binding domains targeting B cell maturation antigen. Our previous reports showed a remarkable efficacy of LCAR-B38M in patients with relapsed/refractory multiple myeloma (RRMM) at a median follow-up of 2 years. Here, we report long-term safety and efficacy data from a median follow-up of 4 years. Methods LEGEND-2 was a phase 1, single-arm, open-label study conducted in four registered sites in China. Seventy-four participants with RRMM received LCAR-B38M treatment. Lymphodepletion was performed using cyclophosphamide or cyclophosphamide plus fludarabine. LCAR-B38M, at a median dose of 0.513 × 10 6 cells/kg, was intravenously administered either in three split infusions or in a single infusion. The primary objective was the safety of LCAR-B38M, and the secondary objective was efficacy. Results As of May 25, 2021, the median follow-up was 47.8 months. All patients experienced ≥ 1 adverse events (AEs). Grade ≥ 3 AEs were observed in 45/74 (60.8%) patients. Cytokine release syndrome (CRS) occurred in 68/74 (91.9%) cases; 7 (9.5%) had grade ≥ 3 CRS. One patient experienced grade 1 central nervous system toxicity. The overall response rate was 87.8%. Fifty-four out of 74 (73.0%) patients achieved complete response. The median progression-free survival was 18.0 months, and the median overall survival for all patients was not reached. The median duration of response was 23.3 months. Four patients experienced viral infection more than 6 months post-infusion, and four patients developed second primary non-hematological malignancies at a median time of 11.5 months post-CAR-T cell transfer. Conclusions The 4-year follow-up data of LCAR-B38M therapy demonstrated a favorable long-term safety profile and a durable response in patients with RRMM. Trial registration Clinicaltrials.gov NCT03090659 (retrospectively registered on March 27, 2017); ChiCTR-ONH-17012285.
Re: Sounak Gupta, Christine M. Lohse, Ross Rowsey, et al. Renal Neoplasia in Polycystic Kidney Disease: An Assessment of Tuberous Sclerosis Complex–associated Renal Neoplasia and PKD1/TSC2 Contiguous Gene Deletion Syndrome. Eur Urol 2022;81:229–33
Authors: Yang Zhao, Wenda Wang, Yushi Zhang
Journal: European Urology (2022)
Droplet Microarray Based Screening Identifies Proteins for Maintaining Pluripotency of hiPSCs
Authors: Yanxi Liu, Sarah Bertels, Markus Reischl, Ravindra Peravali, Martin Bastmeyer, Anna A. Popova, Pavel A. Levkin
Journal: Advanced Healthcare Materials (2022)

Abstract Human induced pluripotent stem cells (hiPSCs) are crucial for disease modeling, drug discovery, and personalized medicine. Animal‐derived materials hinderapplications of hiPSCs in medical fields. Thus, novel and well‐defined substrate coatings capable of maintaining hiPSC pluripotency are important for advancing biomedical applications of hiPSCs. Here a miniaturized droplet microarray (DMA) platform to investigate 11 well‐defined proteins, their 55 binary and 165 ternary combinations for their ability to maintainpluripotency of hiPSCs when applied as a surface coating, is used. Using this screening approach, ten protein group coatings are identified, which promote significantly higher NANOG expression of hiPSCs in comparison with Matrigel coating. With two of the identified coatings, long‐term pluripotency maintenance of hiPSCs and subsequent differentiation into three germ layers are achieved. Compared with conventional high‐throughput screening (HTS) in 96‐well plates, the DMA platform uses only 83 µL of protein solution (0.83 µg total protein) and only ≈2.8 × 10 5 cells, decreasing the amount of proteins and cells ≈860 and 25‐fold, respectively. The identified proteins will be essential for research and applications using hiPSCs, while the DMA platform demonstrates great potential for miniaturized HTS of scarce cells or expensive materials such as recombinant proteins.
Non-synergy of PD-1 blockade with T-cell therapy in solid tumors
Authors: John S Davies, Farrah Karimipour, Ling Zhang, Nisha Nagarsheth, Scott Norberg, Carylinda Serna, Julius Strauss, Shinheng Chiou, James L Gulley, Christian S Hinrichs
Journal: Journal for ImmunoTherapy of Cancer (2022)

Cell therapy has shown promise in the treatment of certain solid tumors, but its efficacy may be limited by inhibition of therapeutic T cells by the programmed cell death protein-1 (PD-1) receptor. Clinical trials are testing cell therapy in combination with
Zanubrutinib versus bendamustine and rituximab in untreated chronic lymphocytic leukaemia and small lymphocytic lymphoma (SEQUOIA): a randomised, controlled, phase 3 trial
Authors: Constantine S Tam, Jennifer R Brown, Brad S Kahl, Paolo Ghia, Krzysztof Giannopoulos, Wojciech Jurczak, Martin Šimkovič, Mazyar Shadman, Anders Österborg, Luca Laurenti, Patricia Walker, Stephen Opat, Henry Chan, Hanna Ciepluch, Richard Greil, Monica Tani, Marek Trněný, Danielle M Brander, Ian W Flinn, Sebastian Grosicki, Emma Verner, Alessandra Tedeschi, Jianyong Li, Tian Tian, Lei Zhou, Carol Marimpietri, Jason C Paik, Aileen Cohen, Jane Huang, Tadeusz Robak, Peter Hillmen
Journal: The Lancet Oncology (2022)